The objective of the proposed research is to study the interaction of narcotic drugs with cyclic nucleotides in the striatum and other brain areas and their relationship in the process of tolerance to and dependence on morphine. Since morphine affects not only cyclic AMP but also cyclic GMP, we investigated the mechanisms involved in regulation of cyclic GMP levels. We found that apomorphine and pilocarpine increase cyclic GMP in both striatum and cerebellum and that haloperidol prevents this effect. On the other hand, dexetimide did not block pilocarpine action. Apomorphine increases cyclic GMP levels to the same degree in both naive and morphine-dependent rats. This finding is in contrast to decreased apomorphine potency to increased cyclic AMP levels in morphine-dependent animals which we observed previously. GABA levels are not changed by apomorphine but they are lower in 24 hr - withdrawn rats than in control and 72 hr - withdrawn animals. The differential effect of morphine dependence and withdrawal on cyclic nucleotides will be further investigated. Specifically, cyclic AMP-dependent protein kinase activities will be compared in naive and morphine dependent animals, effect of specific lesions on morphine-induced nucleotide changes will be studied and localization of these changes will be further investigated. BIBLIOGRAPHIC REFERENCES: Puri, S.K., Volicer, L. and Cochin, J.: Changes in the striatal adenylate cyclase activity following acute and chronic morphine treatment and during withdrawal. J. Neurochem. 27: 1551-1554, 1976. Puri, S.K., Volicer, L. and Lal, H.: Effect of apomorphine on dopamine turnover and adenosine 3',5'-monophosphate content in striatum of morphine-dependent rats. Neuropharmacol. 16: 205-209, 1977.